Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death in the United States. Most of the estimated 32,000 annual new cases in the U.S. and 60,000 annual new cases in Europe will die within a year of diagnosis. There is an urgent need to develop new and better strategies for the treatment of pancreatic cancer. As with other solid tumors, we and others have found that inhibition of VEGF can slow the progression of pancreatic cancer in vivo. However, these studies have also shown that this approach does not completely block tumor associated angiogenesis suggesting that other factors are involved. Clinically, the use of humanized VEGF antibody has demonstrated some utility, but has not provided much survival advantage. Preliminary evidence in our laboratory suggests that CXC chemokines are important mediators of disordered growth and angiogenesis in pancreatic cancer. Several CXC chemokines are potent angiogenic factors and represent a unique family of cytokines that exert promotion of angiogenesis through a single receptor CXC receptor 2 (CXCR2). Blockade of CXCR2 is potentially a powerful strategy to slow angiogenesis and prevent tumorigenesis. We hypothesize that the progression of pancreatic cancer is promoted by the expression of specific angiogenic CXC chemokines and activation of the corresponding receptor, CXCR2; and that inhibition of CXCR2 will delay the growth and metastasis of pancreatic cancer related to inhibition of angiogenesis. We will pursue the following specific aims: Specific Aim I) Determine whether CXCR2 ligands as compared to VEGF correlate with tumor growth in vivo, and whether CXCR2 inhibition abrogates angiogenesis, local growth and metastasis of pancreatic cancer in an orthotopic murine model; Specific Aim II) Determine whether circulating and tumor levels of CXCR2 and CXCR2 ligands in patients with pancreatic cancer are correlated with degree of angiogenesis, stage of disease, and survival. To complete these aims we will perform three experiments in a pancreatic cancer orthotopic model to inhibit CXCR2 by (1) antibody, and (2) growth in a CXCR2-/- murine model. Treatment groups will be compared to treatment against VEGFR2, and in combination, in order to assess the contribution of these two systems. Finally, our large clinical volume of patients with pancreatic cancer will be utilized to evaluate CXCR2 ligands and CXCR2 as these correlate to stage and prognosis. Pancreatic cancer is a devastating disease and will be responsible for more than 32,000 deaths in the United States this year (1). A potential therapy for patients with this disease would be to stop the spread of this cancer by stopping the growth of blood vessels into and around the tumor. This project investigates the impact of two systems responsible for this blood vessel growth, CXC chemokines and VEGF, on the growth of pancreatic cancer and also establishes the relationship of these proteins to pancreatic cancer in patients with this disease. [unreadable] [unreadable] [unreadable]